A selective lesion of the 5-HT axon terminals carried out by injecting i.c.v. 5,7-dihydroxytryptamine (5,7-DHT), prevents the down-regulation of Beta-adrenergic receptors measured in cortical minces after repeated daily injections of imipramine or desipramine. This suggests a functional link (neuronal loop?) connecting 5-HT axons with NE synapses which is operative in the regulation of the NE-receptor function and perhaps participates in the antidepressant action of imipramine and its congeners. The Vmax of the 5-HT reuptake by hippocampal minces is increased when the number of imipramine binding sites is decreased by daily injections of imipramine or desipramine repeated for two to three weeks. Moreover in these minces also the in vitro inhibition of the 5-HT uptake by various imipramine concentrations is attenuated. These findings are consistent with a physiological role of the imipramine binding site and support the working hypothesis that an endogenous effector (endocoid) modulates 5-HT uptake by acting on imipramine recognition sites. A thermostable, nonpeptidic, endocoid that selectively inhibits in a dose-dependent manner 3H-5-HT uptake and 3H-imipramine binding was purified from brain. Crude synaptic membranes of rat brain contain also specific and high affinity binding sites for 3H-mianserin, an atypical antidepressant. The 3H-mianserin recognition sites appear to be different from the 5-HT2 recognition sites labeled by 3H-ketanserin. A 5,7-DHT lesion increases the number of 3H-mianserin recognition sites, while leaves unchanged the 3H-ketanserin sites. The mianserin recognition site appears to be a modulatory site distinct from the 5-HT2 recognition site but cooperating to modulate serotonergic synapses.